rs1161932777
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_StrongPM2PP3_StrongPP5
The NM_023936.2(MRPS34):c.321+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00000658 in 151,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 35)
Consequence
MRPS34
NM_023936.2 splice_donor
NM_023936.2 splice_donor
Scores
2
4
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.39
Genes affected
MRPS34 (HGNC:16618): (mitochondrial ribosomal protein S34) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.5098935 fraction of the gene.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-1772798-C-A is Pathogenic according to our data. Variant chr16-1772798-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 430586.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-1772798-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRPS34 | NM_023936.2 | c.321+1G>T | splice_donor_variant | ENST00000397375.7 | |||
MRPS34 | NM_001300900.2 | c.321+1G>T | splice_donor_variant | ||||
EME2 | NM_001257370.2 | upstream_gene_variant | ENST00000568449.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRPS34 | ENST00000397375.7 | c.321+1G>T | splice_donor_variant | 1 | NM_023936.2 | P1 | |||
MRPS34 | ENST00000177742.7 | c.321+1G>T | splice_donor_variant | 1 | |||||
EME2 | ENST00000568449.7 | upstream_gene_variant | 1 | NM_001257370.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151940Hom.: 0 Cov.: 35
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GnomAD4 exome Cov.: 63
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151940Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 74192
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Leigh syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | Mitochondrial Research Group, Murdoch Children's Research Institute | Jun 29, 2017 | - - |
Combined oxidative phosphorylation deficiency 32 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 25
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at